Aims: Polymorphonuclear leukocytes (PMN) play an important role during inflammation in cardiovascular diseases. Human neutrophil peptides (HNP) are released from PMN granules upon activation and are conventionally involved in microbial killing. Recent studies suggested that HNP may be involved in the pathogenesis of vascular abnormality by modulating inflammatory responses and vascular tone. Since HNP directly interact with endothelium upon release from PMN in the circulation, we tested the hypothesis that stimulation with HNP of endothelial cells modulates the expression of vasoactive byproducts through altering cyclooxygenase (COX) activity. Methods and results: When human umbilical vein endothelial cells (HUVEC) were stimulated with purified HNP, we observed a time- and dose-dependent increase in the expression of COX-2 while COX-1 levels remained unchanged. Despite an increased expression of COX-2 at protein level, HNP did not significantly enhance the COX-2 activity thus the production of the prostaglandin PGI₂. HNP significantly induced the release of endothelin-1 (ET-1) as well as the formation of nitrotyrosine. The HNP-induced COX-2 and ET-1 production was attenuated by the treatment with the oxygen free radical scavenger N-acetyl-L-cysteine, and the inhibitors of p38 MAPK and NF-B, respectively. The angiontensin-II pathway did not seem to be involved in the HNP-induced upregulation of COX-2 and ET-1 since the use of the angiotensin converting enzyme inhibitor enalapril had no effect in this context. Conclusion: HNP may play an important role in the pathogenesis of inflammatory cardiovascular diseases by activating endothelial cells to produce vasoactive byproducts as a result of oxidative stress.